An Open-Label Phase I/II Dose Finding Study to Evaluate the Safety, Tolerability, and Preliminary Efficacy of Striatal Administration of AB-1001 in Adult Subjects With Early Manifest Huntington's Disease (HD)
试验速览
- 阶段
- 1 期
- 状态
- 进行中（未招募）
- 发起方
- 入组人数
- 5
- 试验地点
- 2
- 主要终点
- Incidence of Dose-Limiting Toxicities (DLTs), Treatment-Emergent Adverse Events (TEAEs), and Serious Adverse Events (SAEs)
研究概览
简要总结
A Phase I/II Dose-Finding Study to Evaluate Striatal Administration of AB-1001 (previously BV-101) in Adults with Early Manifest Huntington's Disease
详细描述
This is a Phase I/II, first-in-human, open-label study to evaluate the safety, tolerability, and preliminary efficacy signals in subjects with early manifest HD following treatment with one-time intracerebral bilateral injections of AB-1001 within the striatum (caudate and putamen).
This study consists of 2 parts: Dose-Finding Part and Expansion Part; each part consists of 3 phases: Screening Phase (8 weeks, with extension to 12 weeks to accommodate scheduling if needed), Treatment and Initial Follow-Up Phase (52 weeks) and Long-Term Follow-Up Phase (4 years). In the Dose-Finding Part, 2 dose titers will be tested in 3-6 subjects in each cohort. Once a dose is selected based on Dose-Limiting Toxicities, an additional 6 subjects will be enrolled into the Dose Expansion Part.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 65 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Male or Female subjects between ages 18 and 65 years (both inclusive) at time of consenting, able to provide Informed Consent and able to understand and comply with all study procedures.
- •Documented genetic confirmation of pathological CAG expansion in the huntingtin gene ≥
- •Early manifest HD as defined by a UHDRS total functional capacity (TFC) score of 9 to 13 and a diagnostic classification level (DCL) of 4, or a DCL of 3 if present with cognitive impairment and clear evidence of disease progression.
- •Striatal MRI volumes per hemisphere: Putamen ≥ 2.3 cm3 (per side); Caudate ≥ 1.7 cm3 (per side) on Screening MRI.
- •All HD concomitant medications stable for at least 30 days prior to screening at the investigator's discretion.
排除标准
- •Prior or ongoing medical condition, physical findings, ECG findings, or laboratory abnormality that, in the investigator's opinion, would impact subject's safety and compliance with the study procedures.
- •Metastatic neoplasms within the five years prior to screening.
- •Presence of clinically relevant immunologic, hematologic, hepatic, cardiac, or renal disease at the time of screening as per investigator's clinical judgment.
- •Current untreated and unstable depressive disorder or a serious mood disorder requiring hospitalization.
- •History of prior suicide attempt or imminent risk of self-harm based on investigator's judgment or with a "yes" answer on item 4 or 5 on the Columbia Suicide Severity Rating Scale (C-SSRS).
- •Patients with history of confirmed stroke, known intracranial neoplasms, vascular malformations, or intracranial hemorrhage.
- •Subjects not deemed suitable for the surgical procedure as per the Neurosurgeon's judgment.
- •Any history of gene therapy, cell transplantation or any other experimental brain surgery.
- •Any RNA or DNA targeted HD specific investigational agents such as antisense oligonucleotides within 6 months prior to screening.
- •Subjects unable to tolerate or unwilling to undergo multiple lumbar punctures.
- •Participation in any clinical trial of an approved or non-approved investigational drug or intervention within 12 weeks or 5 half-lives whichever is longer prior to treatment.
研究组 & 干预措施
Cohort 2
High-dose of AB-1001
干预措施: AB-1001 Gene Therapy (Genetic)
Cohort 1
Low-dose of AB-1001
干预措施: AB-1001 Gene Therapy (Genetic)
结局指标
主要结局
Incidence of Dose-Limiting Toxicities (DLTs), Treatment-Emergent Adverse Events (TEAEs), and Serious Adverse Events (SAEs)
时间窗: Through Week 52
The incidence of DLTs, TEAEs, and SAEs will be measured according to protocol specifications.
次要结局
- Mutant Huntingtin protein (mHTT)(At Week 52)
- Neurofilament light chain (NfL)(At Week 52)
- 24OH cholesterol(At Week 52)
- Positron emission tomography (PET) fluoro-deoxyglucose (FDG) striatal profile(At Week 52)
- Composite Unified Huntington Disease Rating Scale (cUHDRS)(At Week 52)
- Magnetic resonance spectroscopy (MRS) metabolic profile(At Week 52)
- Anatomical and volumetric measures of brain regions impacted by HD as assessed by MRI(At Week 52)